Alzheimer's Disease (AD) is the most frequent cause for dementia among the aged, with an incidence of about 10% of the population in those above 65 years of age. With increasing age, the probability of disease also rises. Globally, there are about 15 million people affected with the disease and further increases in life expectancy are expected to increase the number of people affected with the disease to about three-fold over the next decades. In view of the foregoing, there is a tremendous and immediate need for a treatment for AD. With such treatment, affected patients may be able to maintain a functional and active lifestyle for many years beyond that which is not possible without such treatment. Thus, not only are there financial implications for such a treatment but “quality of life” implications as well, for the patients as well as for their caregivers.
From a molecular point of view, AD is characterized by a deposit of abnormally aggregated proteins. In the case of extra-cellular amyloid plaques, these deposits consist mostly of amyloid-β-peptide filaments (Aβ), and in the case of the intracellular neurofibrillary tangles (NFTs), mostly of the tau protein. AD is also characterized by an increased neuronal expression of RAGE. RAGE is a multi-ligand receptor of the immunoglobulin family which functions as a signal-transducing cell surface acceptor for Aβ.
Aβ40 infusion in mice has been shown by several groups to lead to vasoconstriction of cerebral vessels and a decrease of cerebral blood flow (CBF). Patients suffering from AD also have a decreased cerebral blood flow. In mouse models of AD where the transgenic animals overexpress the protein Amyloid Precursor Protein (APP) that leads to disease causing plaque formation, RAGE has been implicated as a pathogenic factor in the disease progression (Deane et al. Nature Medicine 9(7) pp 907-913, 2003; Arancio et al. EMBOJ, 1-10, 2004).
RAGE has been shown to bind to Aβ-peptides. Inhibition of this interaction suppresses accumulation of Aβ in the transgenic animal model; therefore RAGE is believed to be involved in AD. Treatment with sRAGE (soluble RAGE) as well as anti-RAGE antibodies has been shown to lower plaque numbers (Deane et al, 2003). Blocking the interaction of RAGE with amyloid by antibodies could become a treatment for AD patients; however, existing polyclonal antibodies generated from animal serum are not suited for the chronic treatment of humans.
Interaction of RAGE with Aβ is disclosed in WO 2006/077101 A1, which describes competition of RAGE lacking the v-domain for the binding of Aβ to RAGE, as well as the competition of peptides representing parts of the C-terminal domain of RAGE, mostly the C1-domain. Interaction of anti-RAGE antibodies with the v-domain of RAGE is disclosed in WO2007109749(A2); which also describes that binding of different ligands (S100b, HMGB1 (High Mobility Group Box 1 protein), amyloid aβ) would bind to RAGE via binding to this domain.
WO 2008/137552 A2 discloses certain monoclonal anti-RAGE antibodies binding to different domains of RAGE. Most of said antibodies inhibit the interaction of human RAGE and a complex of HMGB1 and CpG DNA.
WO2006/077101 relates to the identification, functionality and use of peptides designated AGER-RME and AGER-CDP of RAGE. Said peptides are inter alia applicable for identifying and preparing RAGE binding ligands like anti-RAGE antibodies.
The present invention describes novel monoclonal antibodies that bind to the C-domains of RAGE and the specific interaction and competition with the binding of Aβ with monoclonal antibodies for the C1 and C2-domain in RAGE.